Despite significant progress in understanding the genetic basis of familial Alzheimer's disease (AD), the causes of sporadic cases have not been well-defined. Many environmental factors (including heavy metals, Infectious agents, and head injury) have been proposed to underlie this neurodegenerative disorder but no plausible mechanisms have been clearly identified. With regard to infectious agents, speculation has often centered on the neurotropic herpesviruses, with herpes simplex virus 1 (HSV1) considered a likely candidate. We found that an internal sequence of the HSV1 glycoprotein B (gB) bears striking sequence identity/homology to the carboxyl-terminal region of the Beta-amyloid (ABeta) peptide. Our preliminary data indicate that the physical and biological properties of this gB fragment are comparable to ABeta and we demonstrate that the gB peptide forms beta- pleated sheets, self-assembles into fibrils that are thioflavin 5- positive and ultrastructurally indistinguishable from ABeta, and is toxic to primary cortical neurons at doses comparable to ABeta. Notably, this same viral protein also shares homology to apolipoprotein E. Therefore, within the same viral protein exists homology to two of the most Important proteins correlated with the pathology of AD. These intriguing findings may suggest a possible role for an infectious agent in the pathophysiology of sporadic cases of AD. With this knowledge, the proposed experiments are designed to evaluate a possible role for a viral agent as a cofactor in AD. The specific aims of this proposal are [1] to determine whether the gB protein is processed under physiological conditions to yield the ABeta-like region, [2] to determine if the gB protein exists in the AD brain, [3] to determine if high levels of gB expression in the brains of transgenic mice leads to AD-like neuropathology, Establishing a correlation between herpesvirus and AD would clearly provide a novel approach to therapeutic intervention and would warrant clinical investigations into the efficacy of antiviral agents in the treatment of some AD cases. Further, it would indicate that it might eventually be possible to develop effective vaccines to prevent or delay the onset of some sporadic AD cases. The funds provided by this RO3 grant will allow us to obtain the necessary preliminary data that should make it possible to obtain funding through an RO1 grant in the near future.